Each year over 500,000 children become HIV-1-infected in sub-Saharan Africa after exposure to maternal virus in blood, genital secretions, and breast milk. Identifying feasible, safe, and affordable interventions that prevent mother-to-child transmission remains a priority for HIV-1 prevention research. We propose a randomized clinical trial to determine whether incorporating HSV-2 suppression with valacyclovir into standard prevention of mother-to-child HIV-1 transmission regimens will reduce plasma, genital, and breast milk HIV-1 RNA levels and risk of transmission among HIV-1-infected and HSV-2-seropositive women. We plan to enroll a total of 148 HIV-1 and HSV-2 co- infected pregnant women with CD4>200 cells/5l who seek antenatal care prior to 32 weeks gestation at a clinic in Nairobi, Kenya. Women will be randomized to receive either valacyclovir suppressive therapy or placebo at 34 weeks gestation and mother- infant pairs will be followed for 12 months postpartum. Follow-up visits will be scheduled at 38 weeks gestation, birth, at 2, 6, 10 and 14 weeks, and at 6, 9, and 12 months postpartum. Maternal blood, genital and breast milk specimens obtained at follow-up visits will be used to determine the effect of valacyclovir suppressive therapy on HIV-1 RNA in these compartments. Infant filter paper specimens for HIV-1 DNA assays will be collected at birth, and 6 weeks, 14 weeks, 6, 9, and 12 months of age in order to compare the proportion of infants acquiring HIV-1 in the two study arms and determine the timing of HIV-1 infection. In addition, we will monitor maternal and infant renal and liver function in preparation for a larger randomized clinical trial in Africa. We anticipate that results of this study will help guide the design of a multi-site clinical trial with adequate power to determine the effect of HSV-2 suppression on vertical transmission of HIV-1 infection.Project Narrative HSV-2 suppression to reduce maternal plasma, genital and breast milk HIV-1 levels There is growing evidence that HSV-2 contributes significantly to risk of mother-to-child HIV-1 transmission in resource-limited settings. In the proposed study, we will collect preliminary data on HSV-2 suppressive therapy during pregnancy and postpartum in anticipation of a multi-site randomized clinical trial using valacyclovir to prevent infant HIV-1 acquisition in utero, intrapartum and via breast milk. Such a trial has the potential to impact prevention of mother-to-child HIV-1 transmission (PMTCT) policies and substantially reduce vertical HIV-1 transmission in regions most affected by the AIDS epidemic.